Theophylline derivatives

ABSTRACT

7-(N-methyl-N-( Beta -phenylethyl)-3-aminopropyl)-theophylline compounds substituted on the phenyl nucleus by chlorine, hydroxyl or lower alkoxy and preferably also by fluorine, trifluoromethyl or another chlorine or hydroxyl are disclosed to have excellent anti-allergy and bronchio-dilatatory efficacy without sedative side effects.

United States Patent [1 1 Dengel et al.

[ Dec. 16, 1975 THEOPHYLLINE DERIVATIVES [75] Inventors: FerdinandDengel, Wilhelmsfeld;

Oskar Ehrmann, Mannheim; Ludwig Friedrich, Mannheim; Frank Zimmermann,Mannheim, all of Germany [73] Assignee: Knoll A.G. Chemische Fabriken,

Ludwigshafen (Rhine), Germany [22] Filed: Aug. 3, 1973 [21] Appl. N0.:385,320

[30] Foreign Application Priority Data Aug. 8, 1972 Germany 2239012 [52]US. Cl. 260/256; 260/253; 424/253 [51] Int. C07D 473/08 [58] Field ofSearch 260/256 [56] 1 References Cited UNITED STATES PATENTS 3.245.9944/1966 Klingler et al. 260/256 FOREIGNPATENTS OR APPLICATIONS 1,237,5783/l967 Germany 260/256 Primary Examiner-Donald G. Daus AssistantExaminer-Anne Marie T. Tighe Attorney, Agent, or FirmCurtis, Morris &Safford -2 Claims, No Drawings THEOPHYLLINE DERIVATIVES The presentinvention relates to pharmacologically active basic substituedtheophylline derivatives.

It is known that certain basic substituted xanthine derivatives havevaluable pharmacological properties. Thus, for example, [N-methyl-N-(S',4'-dimethoxybenzyl)-/3-aminoethyl]-theobromine possesses both coronarydilatory and blood pressure reducing properties.

According to the present invention, there are provided compounds of theformula I in which R represents chlorine, hydroxyl or lower alkoxy (of lto 4 carbon atoms) and R represents hydrogen in the 4-position orfluorine, chlorine, trifluoromethyl, or hydroxyl in any position of thering. Compounds in which R and R are substituted in the 3- and4-positions and in which R is fluorine, chlorine, trifluoromethyl orhydroxyl are preferred.

Since these compounds possess good anti-allergy and bronchio-dilatatoryproperties without sedative side effects, the present invention alsoprovides pharmaceutical compositions comprising these compounds inassociation with pharmaceutically acceptable carriers.

The present invention also relates to processes for preparing suchcompounds.

According to a first embodiment of the process of the 5 presentinvention, theophylline is reacted with a halogenoalltylamine of theformula (II).

wherein Hal represents halogen and R and R have the above-statedsignificance, in the presence of a hydrogen halide bonding agent.

According to a third embodiment of the process of the present invention7-(3-methylaminopropyl)-the0phylline is reacted with anucleus-substituted phenylethylhalide of the formula IV 5 Hal--CH CHAccording to a fourth embodiment of the process of 40 the presentinvention, a secondary amine of the formula V 5 is methylated, in aknown manner on the basic nitrogen atom.

According to a fifth embodiment. a compound of the formula I substitutedon the benzene nucleus by an alkoxy-, methylenedioxy-, benzyloxyorbenzylcarboxy-group is subjected to ether splitting.

ln the first embodiment of the process. an alcoholic' solution isemployed. using an alkali alcoholate as the condensing agent or.alternatively. an aqueous alcoholic solution using soda lye may beemployed. In this case. the starting materials are heated under refluxfor a period of time with agitation. It has been found particularlyadvantageous to stir a suspension of theophylline. dry potassiumcarbonate and a compound of the Formula ll in an inert solvent.preferably acetone or butanonc. at the boiling temperature of thesolvent.

In the second embodiment of the process. it has been found that as thehydrogen halide bonding agent. the

addition of a second mol of the base (111) suffices. The

reactants are heated together for some hours. in an oil bath. to atemperature of about 140 C. If a suitable hot solvent is then added.such as toluene or xylene. one mol of the hydrogen halide salt of thebase 111 is precipitated out in a crystalline form. and may be filteredoff. The filtrate then contains the basic product of the process. It isalso possible to carry out the reaction in boiling xylene, or with areactive halide in toluene. In

this case. instead of utilizing an additional mol of the base (111 drycalcium carbonate or a tertiary base such as pyridine or triethylamineis employed as an acidbonding agent. These working conditions also applyto the third embodiment of process.

The introduction of the methyl group into a secondary base of Formula Vfor conversion into a compound of Formula I in accordance with theinvention may be carried out according to the fourth embodiment of theprocess by treatment with a methyl halide or dimethylsulfate. followedby boiling with formalin or paraformaldehyde and formic acid. Themethylation may also be carried out with an alcoholic solution of thesecondary base V mixed with formaldehyde in the presence of palladium ornickel catalyst by shaking with hydrogen. or by treating with analuminum amalgam or sodium borohydride or suitable reducing agent.

In order to obtain the products in accordance with the invention whichhave free phenolic hydroxyl groups. the compounds of Formula I. if Rand/or R is alkoxy. benzyloxy or benzylcarboxy or. deviating from theFormula 1. jointly form a methylene dioxide group. are treated withaqueous hydrogen halide acids under the influence of heat. To improvethe solubility, it is possible. if necessary. to add a suitable solventsuch as glacial acetic acid or acetic anhydride. lf hydrochloric acid isused as the demethylating agent. then it is neces sary. in some cases.to heat under pressure. If the starting substances are benzyloxy orbenzylcarboxy compounds. then these may also be converted. byhydrogenation with palladium catalysts. into the phenolic products.

' y A further possibility of carrying out the process of the presentinvention consists in the use ofa bonded hydrogen halide acid in theform ofa salt such as. for example. pyridinehydrochloride. The procedureis such that the reactants are fused. possibly with the addition of asuitable solvent such as glacial acetic acid or acetic anhydride. at anelevated temperature.

The ether splitting may be carried out with an organic acid halideeither in the presence or absence of a catalyst. whereby the reactivityincreases in accordance with the sequence chloride bromide iodide. Ascatalysts. both metal and non-metal halides may be used. Zinc chloride.stannic-(IV)-chloride and boron tri-fluoride are particularly suitable.A further possibility consists in the use of a electrophilic metalhalide such as. for example. aluminum chloride or bromide.

' The new compounds possess a histaminolytical effect over a widespectrum against both endogenic (anaphylactic) and exogenic histaminereactions. These properties make them valuable pharmaceuticals in thetreatment of a number of diseases. such as bronchial asthma. urticaria.hay-fever. skin complaints and allergies. Moreover. the acute toxicity(see Table 2. Column C) of the compounds relative to theirhistaminological effect (see Table 1. Column A). and hence the range oftherapeutic use of the new substances (see Table 2. Column CA). incomparison to known substances is considerably better. Of greatimportance is the fact that the compounds of the invention. unlikeantihistamines heretofore proposed. do not have sedative side-effects.

The histaminololytic effectiveness of the compounds was tested accordingto the method of H. Konzett and R. Roessler [Arch. exp. Path. Pharm.195. 71 (1940)] on the broncho-spasms of guinea pigs. In Table 1. ColumnA. there are listed the dosages which reduce the number ofbroncho-spasms by half (ED-.

On the isolated ileum of a guinea pig. the new compounds show a highhistaminolytic effect. as may be shown by utilizing the method of R.Magnus [Pfiuegers Arch. ges. Physiol. 102. 123 (1904)]. Column B ofTable 1. lists the concentrations in ,ug/ml bath liquid which completelystop the initial spasm. The compounds which have proved particularlyeffective are those in which the ortho positions of the phenyl group areunsubstituted and the meta and para positions are both substituted. Ofthese compounds, the compounds identified as Nos. 3 and 4 in Table 1 arethe most effective.

For therapeutic application, the new substances may be administered inthe form of ampoules. tablets, sweets or inhalents. The preferred doseis between 0.1 to 1.0 mg/kg orally or 0.01 to 0.1 mg/kg parenterally.per day.

TABLE 1.

CH I 3 CH c No. R, R- R R Example 1 .A B

. mg/kg ag/ml 1 Cl H H Cl 2. 9 (1.4 10.0 2 H Cl OCH H 14 0.064 1.0 3 HC1 C1 H 1.10 0.012

17.19 4 H Cl OH H 20 0.004 0.1 5 Cl H C1 H 3. 11 0.065 1.0 6 H OCH;, ClH '15 0.055 0.05 7 Cl OCH H H 16 0.5 8 H OH Cl H 21 0.035 1.0 9 Cl OH HH 22 1.0 10 H OH OH H 23 0.18 v 50 l 1 Cl H H H 4 0.23 50.0 12 H Cl H H5 0.04 0.5 13 H r F OCH H 7 0.05 0.5 14 H CF;, H H 8 0.065 0.5 15Theophylline (Comparison substance) 3.0 1000 16 Bamiphylline (Comparisonsubstance) 10.0 l00.0 l7 Cinnarizine (Comparison Substance) 0.45 5.0

, TABLE 2.

Substance No. Acute toxicity. albino mouse Therapeutic LD in mg/kg i.v.range hols. from aromatic carboxylic acids or their esters by 40 Some ofthe starting substances used for preparing the new compounds have nothitherto been described. They are obtainable as follows:

The alkylamine halide of Formula [I is obtained by condensation of thecorresponding nucleus-substituted B-phenylethylamine with3-chloropropanol. The secondary aminoalcohols thus formed are then, in aconventional manner. such as by means of formaldehyde and formic acid.methylatedon the nitrogen atom and subsequently thehydroxyl group issubstituted by treatment with thionyl chloride. 1f the N-monomethylderivative of the ,B-phenylethylamine (Formula 111) is used. tertiaryaminoalcohols are obtained'in a single step. and the methylation of thenitrogen is unnecessary.

The preparation of 7-(3-halogenopropyl)-theophylline and 7-(3-aminopropyl)-theophylline have already been described.

7-(3-methylaminopropylene)-theophylline as a free base may be preparedfrom 8-(3-halogenopropyl)- theophylline. The latter is first condensedwith N- methylbenzylamine to form 7-[3-(N-methyl-N-benzylaminopropyl]-theophylline and the benzyl group is subsequently removedwith Pd/H The compounds of .the Formula [11 may be prepared in variousways. Hence, nucleus-substituted benzene compounds are often converted,by treatment with formaldehyde and hydrochloric acid chloromethylationinto the analogous benzyl chlorides. These benzyl chlorides may also,beprepared by way of benzyl alcoreduction with lithium alanate (lithiumaluminum hydride) or from nucleus-substituted aldehydes bycatalytichydrogenation or treatment with reducing agents. followed bychlorination of the benzyl alcohols. From the benzyl chlorides, thecorresponding benzyl cyanides are easily obtainable, for example byreacting them with alkali metal cyanides in dimethylformamide ordimethylsulfoxide. The B-phenylethylamine is obtained therefrom, in aknown manner. by catalytic hydrogenation. From the primaryB-phenylethylamines thus obtained in this manner, by treatment of theirbenzocompounds with dimethyl sulfate or iodomethane. or even byreduction of their N-formyl compounds with lithium alanate. the aminesof the Formula 111 may be prepared.

The compounds of the Formula IV are prepared from the above-describednuclear-substituted benzyl cyanides. These are saponified to form thephenylacetic acids. which upon reduction with lithium alanate yieldB-phenylethanols. which are then reacted with thionyl chloride toproduce the required compounds.

The compounds of the Formula V are obtainable in various ways. They may.for example. be produced from nucleus-substituted ,B-phenylethylaminesby reaction with 7-( 3-halogenopropyl )theophylline.

The invention will be further described. by way of example. withreference to the following examples. In all of these. examples. thevalues for the melting points have been corrected.

EXAMPLE 1 7-[N-methyl-N-( 8-3.4-dichlorophenylethyl )-3-aminopropyljtheophylline.

a. Manufacture of the starting materials 1.N-methyl-B-3.4-dichlorophenylethylamine A solution of3-3.4-dichlorophenylethylamine (41.2 g; 0.217 mol) in toluene is mixedwith 12.0 g formic acid (0.2604 mol or 1.2 X 0.217 mol) and boiled for 4hours under reflux utilizing a water separator. 8.4 ml water are removedduring this stage. The toluene is then evaporated and the residue isdistilled in vacuo for a yield of 41.0 g. representing 90% of thetheoretical yield. of the N-formyl-compound having a boiling point of168 to 171 C/0.02 Torr. The thus-obtained formamide (41 g; 0.188) isdissolved in 200 ml. tetrahydrofuran and added dropwise. with stirringonto a boiling suspension of 1 l. of lithium alanate (lithium aluminumhydride. 2 X 0.188 mol) in 200 m1. tetrahydrofuran in a three-neckedflask. The boiling is continued for 4 more hours and the product isdecomposed by adding water and sodium lye dropwise thereto. Extractionis preformed. The aluminum hydroxide is filtered off 11. N-methyl-1\l(B-3 ,4-dichlorophenylethyl )-3-aminochlorp ropane.

N-methyl-B-3.4-dichlorophenylethylamine (133.5 g;- 2 X 0.328 mol) and3-chloropropano1. (31 g; 0.328 mol) in toluene are boiledunder reflux;with agitation for 24 hours. After separating the precipitatedN-methyl-B-3.4-dichloroethylamine-hydrochloride. the N- methyl-N-( 3-hydroxylpropyl )-B-3..4-'dich1oropheny1ethylamine which remains in theform of an oil after evaporation of the solvent. is absorbed inchloroform. and mixed dropwise with 43.0 g. thionyl chloride (1.2 X0.328 mol). The mixture is then boiled for 2 hours under reflux. Afterevaporating the chloroform. the reaction product is absorbed in hotacetone. On cooling. the hydrochloride of the N-methyl-N-(B-3.4-dichlorophenylethyl)-3-aminochloropropane. having a melting point of 145to 146 C precipitates out. A yield of 73.9 g. representing 76.2% of thetheoretical yield, is obtained. The free base boils at 1 12 to 1 16C/0.2 Torr and its refractive index (u is 1.5392.

b. Preparation of the end product.

N-methyl-N-(,B-3.4-dichlorophenylethyl)-3-aminochloropropanehydrochloride (158.6 g; 0.5 mol) is converted into the free base and thelatter dissolved in 100 ml; toluene. Over a period of minutes. this isadded dropwise 'to a mixture. boiling under reflux, of 250 isopropanol(250 ml). sodium hydroxide (20 g; 0.5 mol). water 14 ml) andtheophylline (90.5 g; 0.5 mol). Boiling under reflux is continued for 3hours. and the precipitated sodium chloride is filtered off under suc fisopropanol; a yield of 200 g. representing 83.4% of the theoreticalyield of the salt. is obtainedwhich has a melting point of 225 to 228 C.This salt contains 1.5 mol HCL per mol base and its aqueous solution isstrongly acidic. If during production of the salt, an excess of hydrogenchloride is avoided by accurately neutralizing the free base. the saltprecipitates out having a composition which contains 1 mol of HCL permol of base. The salt has the same melting point but its aqueoussolution is neutral.

The above-described condensation of theophylline with N-methyl-N-B-(3,4-dichlorophenylethyl )-3- aminochloropropane may also be carried outusing acetone or butanone as the solvent and dry potassium carbonate asthe substance to remove the hydrogen halide.

EXAMPLE 2 7-[N-methyl-N( ,8-2,6-dichlorophenylethyl )-3-aminopropyl]-theophylline.

a. Preparation of the starting materials.

1. N-methyl-B-2.6-dichlorophenylethylamine This compound is obtainedfrom fl-dichlorophenylethylamine [J. Augstein et al.. J. Med. Chem. 101967) 399] by reduction of its N-formyl compound with lithium alanate asdescribed in Example 1 (a) l. The hydrochloride melts at 171 to 174 C.

11. N-methyl-N-( ,8-2.6-dichlorophenylethyl )-3-aminochloropropane Thecompound is obtained from N-methyl-B-Zbdichlorophenylethylamine in amanner analogous to that described in Example 1 (a) 11, that is to sayby condensation with chloropropanol and subsequent treatment of theaminoalcohol with thionyl chloride. The hydrochloride melts at 168 to170 C.

b. Preparation of the end product.

EXAMPLE 3 7-[N-methyl-N-( B-2,4-dichlorophenylethyl )-3-aminopropyl]-theophylline.

I a. Preparation of the starting material 1.N-methyl-B-2,4-dichlorophenylethylamine This compound is obtained from[3-2.4-dichlorophenylethylamine [W. N. Cannon et al., J. Org. Chem.

9 22 1957) 1323] by reduction of its N-formyl compound with lithiumalanate. The hydrochloride melts at 183 to 185 C.

II. N-methyl-N-( B-2,4-dich lorophenylethyl )-3-aminochloropropane Thiscompound is obtained in a manner analogous with that described inExample 1 (a), from N-methyl-B- 2,4-dichlorophenylethylamine bycondensation with 3'-chloropropanol and subsequent treatment of theaminoalcohol with thionyl chloride. Its dioxalate melts at 152 to 154 C.

b. Preparation of the end product.

the theoretical yield is obtained.

EXAMPLE 4 7-[ N-methyl-N-( B-Z-chlorophenylethyl )-3aminopropyl-theophylline.

A three-necked 1 liter flask is provided with a stirring mechanism,athermometer, a dropping funnel, a gas inlet pipe and a riser pipe. Theflask is charged with 7-(3-bromopropyl) theophylline (126.5 g;' 0.42mol) [l-I. Priewe et al., Chem. Ber. 90 (1957) 1951] andN-methyl-B-2-chlorophenylethylamine 142.7 g; 2 X 0.42 mol) [R. Huisgenet al., Chem. Ber. (1959) 210] which are heated together in anatmosphere of nitrogen with initial stirring, for 90 minutes on an oilbath to a temperature of 145 C. Subsequently atl about 120 C., 600 ml.dry toluene are run in and the mixture is stirred until cooled.N-methyl-B-2-chlorophenylethylamine hydrobromide (100.2 g) is extractedtherefrom which is precipitated as white crystalline powder and has amelting point of 105 to 107 C. The toluene filtrate is washed withwater. The toluene phase is shaken out with 500 ml. 1N HCL and the baseis extracted therefrom. The aqueous acid solution is mixed withconcentrated soda lye, the base is absorbed in toluene'and, after dryingover potassium carbonate, is evaporated in vacuo. The residue whichremains is 7-[N-methyl-N- (B-2-chloro'p henylethyl )-3 -aminopropyl-theophylline, which crystallizes on standing. A yield of 133 g,representing 81% of the theoretical yield is obtained. A sample of thesubstance, after crystallization from ether melts at 85 to 90 C. Duringdistillation in a bulb tube, it is converted at about 200 to 210 c. (airbath temperature) 0.001 Torr,into a bright yellow, viscous oil having an11 of 1.5740; It is chromatographically ure. 1 1 1 p If 101 g of thissubstance is dissolved in 400 ml isopropanol and hydrogen chloride gasintroduced to cause a weak acid reaction, the hydrochloride isprecipitated as a white crystalline powder. After crystallization frommethanol 56g of the hydrochloride, having a melting point of 232 to 235C., are obtained. By concentrating the mother liquor, a further 34.6 gare obtained. By dissolving the substance in methanol/e- 10 thanol (1:2)and adding oxalic acid, the dioxalate is obtained which, aftercrystallization from methanol, melts at l84.5 to 188 C. Instead of7-(3-bromopropyl)-theophylline, 7-(3-chloropropyl)-theophylline may beemployed. The reaction time thenamounts to 3 hours.

EXAMPLE 5 7-[N-methyl-N-([SJ-chlorophenylethyl )-3aminopropyl]-theophylline.

In a manner similar to that'described in Example 4,7-(3-bromopropyl)-theophylline 126.5 g; 0.42 mol) is condensed withN-methyl-B-3-chlorophenylethylamine (142.7 g; 2 X 0.42 mol) [R.l-Iuisgen et al., Chem. Ber. 92 (1959) 210] and then worked up. Afterseparating the precipitated N-methyl-B-3-chlorophenylethylaminehydrobromide, there is obtained 7-[N-methyl-N-(B-3- chlorophenylethyl)-3-aminopropyl]-theophylline 15 l g) as a thick, pale yellow oil whichis purified by fractional distillation. The yield of pure substance thusobtained is 104 g, which represents 64% of the theoretical yield. Thepure substance boilsat 218 to 220 C/0.01 Torr and melts, aftercrystallization from isopropanol, at 735 to 745 C. The refractive index(r1 is 1.5750.-

The hydrochloride is precipitated by passing hydrogen chloride gas" intoisopropanol solution and is obtained as a white crystalline powder whichmelts, after EXAMPLE 6 7-[ N-m ethyl-N-( ,8-4-fluorophenylethyl)-3-aminopropyl ]-theophylline.

In a manner analogous to that described in Example 4,7-(3-bromopropyl)-theophylline (301.2 g; 1 mol) andN-methyl-B-4-fluorophenylethylamine (306.2 g; 2 mol) [C. M. Suter etal., J. Am. Chem. Soc. 63, 609 (1941)] are condensed together. Theprecipitated N- methyl-B-4-fluorophenylethylamine hydrobromide isseparated off and the base thus obtained is purified by vacuum At 226C/0.03 Torr, a yield of 280.5 g, representing 74% of the theoreticalyield, of 7-N-methyl-N- B-4-fluorophenyletliyl )-3 -aminopropyl]-theophylline is converted into a pale yellow viscous oil, which iscrystallized from an ether solution and melts at 59 to 61 C.

If the compoundthus obtained is dissolved in methanol, and an excess ofhydrogen chloride is introduced, a spongy white salt is precipitatedwhich contains 2 mols HCL per mol base and melts under rapid heating at242 to 244 C.: Its aqueous solution is strongly acidic; a 5% solutionhaving a pH of 0.85. If, on the other hand, the methanol solution of thebase is neutralized with exactly one equivalent of hydrogen chloride,the monohydrochloride is precipitated. This, after crystallizing frommethanol, melts at 237 to 239 C. under rapid heating and its aqueoussolution is substantially neutral, a 5% solution having a pH of 6.0. Thedioxalate is obtained and crystallized from ethanol and has a meltingpoint of 176 to 177.5 Cv

EXAMPLE 7 7-[N-methyl-N-( 3-fluoro-4-methoxyphenylethyl-3- aminopropyl-theophylline.

a. Preparation of the starting materialN-methyl-B-3-fluoro-4-methoxyphenylethylamineB-3-fluoro-4-methoxyphenylethylamine (477.7 g; 2.82 mol) [K. Kraft. Ber.84. 150 (1951)] and 98% formic acid (146 g; 1.1 X 2.82 mol) aredissolved in 1 l. toluene and boiled under reflux. The water formedduring the reaction is removed. The remainder, after distillation of thetoluene solution, in N-formyl-B-Elfluoro-4-methoxy-phenylethylamine in ayield of 532 g representing 96% of the theoretical yield. It has aboiling point of 162 C/0.03 Torr and an n 25 of 1.5288.

265.0 g 1.343 mol) of this product is dissolved in 1 1. tetrahydrofuran.The solution is added dropwise with stirring over a period of 1 hour inan atmosphere of a mixture boiling under reflux of lithium alanate (69 g1.8 X 0.75 X 1.343 mol) in 3 l. tetrahydrofuran. The mixture is thenboiled under reflux for 6 hours. The reaction mixture is subsequentlydecomposed by the dropwise addition of water and soda lye. The aluminumhydroxide thus produced is filtered under suction. The filtrate isevaporated, the residue obtained therefrom is dissolved in hydrochloricacid and freed from impurities by shaking with toluene. By addition of40% soda lye, the base is again precipitated. which is then dissolved inbenzene. After evaporation of the solvent, the residue is distilled. At139 to 140 C/16 Torr. N-methyl-B-3-fluoro-4-methoxyphenylethylaminedistils over as a colorless oil having an 11 of 1.5051. 206 g areobtained, representing 84% of the theoretical yield. The hydrochloridewhich is obtained from isopropanol and crystallized from isopropanol andethanol (:1), melts at 181 to 182.5 C.

b. Preparation of the end product If 7-(3-bromopropylene)-theophylline(189.5 g; 0.63 mol) is condensed with N-methy1-B-3-fluoro-4- methoxyphenylethylamine (231 g; 2 X 0.63 mol) in the manner described inExample 4. not only is there obtained 152 gN-methyl-B-3-fluoro-4-methoxyphenylethylamine hydrobromide, but also 182g, representing 74% of the theoretical yield, 7-[N-methyl-N-(B-3-fluoro-4-methoxyphenylet hyl )-3-aminopropyl ]-theophylline having aboiling point of 231 C/0.4 Torr and a refractive index 11 of 1.5527.

The hygroscopic hydrochloride, obtained from ethanolic solution of thebase using hydrogen chloride gas. melts after crystallization frommethanol and ethanol (5:1) at 217 to 218 C.

EXAMPLE 8 7-[ N-methyl-N-( B-3-trifl uoromethylphenylethyl )-3-aminoproply ]-theophy1line a. Preparation of the starting material I.,8-3-trifluoromethylphenylethylamine 3-trifluoromethylbenzyl cyanide(233 g; 1.26 mol) [5. E. Rosenkranz et al.. J. Chem. Eng. Data 8. 327(1963)] is dissolved in 1.2 l. methanol containing ammonia(approximately 80 g) and hydrogenated with Raney-Cobalt at 10()/ 100atms. The solution which is separated from the catalyst is evaporatedand the residue obtained therefrom is dissolved in hydrochloric acid andshaken with toluene to remove impurities. The solution is then mixedwith soda lye. the base thus formed is dissolved in benzene. the solventis evaporated and the residue is distilled. The compound is atransparent oil having a boiling point of 88 C/l-l Torr and an 11 of1.4609. The yield obtained is 195 g. representing 82% of the theoreticalyield.

11. N-methyl-B-3-trifluoromethylphenylethylamineB-3-trifluoromethylphenylethylamine (204 g; 1.08 mol) is dissolved in500 ml. toluene and mixed with 55 g formic acid (1.1 X 1.08 mol). Themixture is azeotropically distilled to yield the N-formyl compound.Afterworking up and distillation. a yield of 211 g. representing 91% ofthe theoretical yield of N-formyl- 3-trifluoromethylphenylethylaminehaving a boiling point of 179 C/14 Torr and an u of 1.4795 is obtained.172.8 g (0.8 mol) of the N-formyl compound is dissolved in 1 1.tetrahydrofuran and reduced as de scribed in Example 1 (a) l with 45.5 glithium alanate (2 X 0.75 X 0.8 mol) in 2 l. tetrahydrofuran. Afterworking up. a yield of 131.5 g. representing 81% of the theoreticalyield, of N-methyl-B-3-trifluoromethylphenylethylamine, having a boilingpoint of 96 to 100 C/14 Torr and an N of 1.4598 is obtained. Thehydrochloride, which is obtained from an ethanol/ether mixture and isrecrystallized from ethyl acetate. melts at 143 to 144 C.

b. Preparation of the end product The reaction of7-(3-bromopropyl)-theophylline (80.1 g; 0.27 mol) withN-methyl-B-trifluoromethylphenylethylamine 108.3 g; 2 X 0.27 mol) iseffected in a manner analogous to that described in Example 4 and yields85.1 g, representing 75.6% of the theoretical yield. of7-[N-methyl-N-(,8-3-trifluoromethylphenylethyl)-3-aminopropyl]-theophyl1ine in the form of a pale yellow viscous oilhaving a boiling point of 210 C/0.05 Torr and an 11 of 1.5373. Whenrecrystallized from diethylether. the base melts at 745 to 76 C. A whitehydrochloride separates from an ethanolic solution of the base afterneutralization with hydrogen chloride gas. After crystallization from amixture of isopropanol and ethyl acetate 1: 1 the salt melts at 169 to171 C. The dioxalate, from ethanol. melts at 161 to 162 C.

EXAMPLE 9 7-[N-methyl-N-( B-Z.6-dichlorophenylethyl )-3-aminopropyl]-theophylline.

a. Preparation of the starting materialN-methyl-B-2,6-dichlorophenylethylamine This compound is obtained bypreparing, by the method described in Example 1 (a) l. the N-formylcompound of ,8-2.6-dichlorophenylethylamine [J Augstein et al., J. Med.Chem. 10, 399 (1967)], and subsequent reduction of the amide withlithium alanate. 62% of the theoretical yield (relative to the primarybase) of the N-monomethyl compound is obtained, which is isolated in theform of hydrochloride having a melting point of 171 to 174 C.

b. Preparation of the end product In a three-necked flask,7-(3-bromopropyl)-theophylline (42.2'g; 0.14 mol) is dissolved in 200ml. toluene. N-methyl-B-2.6-dich1orophenylethylamine (28.7 g; 0.14 mol)regenerated from the hydrochloride obtained in (a), and triethylamine14.2 g; 0.14 mol) are for 16 hours. The triethylamine hydrobromide isprecipitated and filtered under suction. the filtrate being evaporatedin vacuo. The residue obtained therefrom is dissolved in 100 ml. hotisopropanol and mixed with a solution of 12.8 g oxalic acid inisopropanol. On cooling, the dioxalate of the required product isprecipitated. After crystallization from isopropanol. there is obtained28.4 g, representing 46% of the theoretical yield, of 7-[N-methyl-N-(B-2,6-dichlorophenylethyl)- 3-aminopropyl]-theophylline dioxalate havinga melting point of 192 to 195 C. It is also possible to use N-methyl-B-2,6-dichlorophenylethylamine as the acid bonding agent instead oftriethylamine. In such a case. double the stoichiometric quantity mustbe used.

EXAMPLE 7-[N-methyl-N-( B-3 ,4-dichlorophenylethyl )-3-aminopropyl-theophylline 7-(3-bromopropyl)-theophylline (42.2 g; 0.14 mol) andN-methyl-B-3.4-dichlorophenylethylamine (28.7 g; 0.14 mol) prepared asdescribed in Example 1 (a), are condensed in the manner described inExample 9 in the presence of triethylamine and worked up. There is thusobtained 7-[N-methyl-N-( ,8-3,4-dichlorophenylethy1)-3-aminopropyl]-theophy11ine hydrochloride having a melting point of 225to 22 8 C. The yield, after crystallization from isopropanol, is 42.3 g,which is 63% of the theoretical yield.

EXAMPLE 1 1 7-[N-methyl-N-([3-2,4-dich1orophenylethyl-3-amino- I Ipropyl]- theophylline 7-(3-bromopropyl)-theophylline (54.8 g; 0.18 mol)and N-methyl-B-2,4-dichlorophenylethylamine (37.3 g; 0.18 mol) obtainedin the manner described in Examplej3 (a) I are condensed together in thepresence of triethylamine. After working up. there is obtained 50.3 g,representing 60% of the theoretical yield, of the hydrochloride which,when crystallized from methanol.

has a melting point of 225 to 257 C.

EXAMPLE 12 7-[ N-methyl-N-( B-2,5-dic hlorophenylethyl)-3-aminopropyl]theop hylline tained. The compound has a'melting pointof 210 to EXAMPLE 13 7-[N-mcthyl-N-( [3-3.5-dichlorophenylethyll-3-aminopropyl ]the0phylline a. Preparation of the starting material 1.[3-3.5-dichlorophenyleth'ylamine 3.5-dichlorobenzylcyanide (46 g: 0.3mol) [M. B. Pybus et al., Ann. Appln. Biol. 47. 593 (1959)] is dissolvedin 250 m1. methanol which contains about 20 g ammonia and hydrogenatedat 50 atmospheres with Rancy-Cobalt. Separation from the catalyst iseffected and the filtrate is evaporated. The residue obtained therefromis dissolved in hydrochloric acid and nonbasic impurities are removed byshaking with toluene. The base is regenerated by the addition of sodalye, dissolved in ether, dried with sodium hydroxide and thehydrochloride is precipitated by passing hydrogen chloride gas throughit. After boiling with acetone, the salt melts at 233 to 236 C. Theyield is 39 g. representing 89% of the theoretical yield.

ll. N-methyl-B-3,S-dichloroethylamine The base is regenerated from thehydrochloride obtained in Part 1 and by utilizing the method describedin Example 1 (a) I, is converted into the formyl compound. By reductionof this amide with lithium alanate,N-methyl-B-3,5-dichlorophenylethylamine hydrochloride, having a meltingpoint of 194 to 197 C is obtained. The yield represents 96% of thetheoretical yield with respect to the primary base.

b. Preparation of the end product 7-(3-bromopropyl)-theophylline (32.4g; 0.11 mol) and N-methyl-B-3,5-dichlorophenylethylamine (22 g, 0.11mol) obtained from Part 11 above, are condensed together in the mannerdescribed in Example 9 with an equivalent quantity of triethylamine.Triethylamine hydrobromide is precipitated, the toluene filtrate isneutralized, and7-[N-methyl-N-(B-3.5-dichlorophenylethyl)-3-aminopropyl]-theophyllinehydrochloride is precipitated as a white crystalline powder. Aftercrystallization from methanol, there is obtained 28.8 g, which is 58% ofthe theoretical yield, of pure salt having a melting point of 213 to 216C.

EXAMPLE l4 7-[ N-methyl-N-( B-3-chloro-4-methoxyphenylethyl )-3-aminopropyl]theophy1line 7-(3-bromopropyl)-theophylline (50 g; 0.17 mol)and N-methyl-B-3-chloro-4-methoxyphenylethylamine (33.2 g; 0.17 mol) [M.Julia et al., Bull. Soc. Chim. France 1966) 1335] are condensed togetherwith trimethylamine in the manner described in Example 9. After workingup. the toluene solution of the required product is neutralized bypassing hydrogen chloride gas through it and the precipitatedhydrochloride is recrystallized from ethanol. A yield of 47.4 g,representing 62% of the theoretical yield. having a melting point of 245to 248 C. is obtained.

EXAMPLE 15 7-[ N-methyl-N-( ,8-3-methoxy-4-chlorophenylethyl )-3-aminopropyl ltheophylline a. Preparation of the starting material 1.,B-3-methoxy-4-chlorophenylethylamine 3-methoxy-4-chlorobenzylcyanide150 g; 0.83 mol) [5. Munavelli et a1., Bull. Soc. Chim. Fr. 1966 10) 33110-18] is dissolved in 600 ml. methanol containing 50 g ammonia andhydrogenated with Raney-Cobalt at 50 /70 atmospheres. After working upas described in Example 8 (a) l. 202 g (91% of the theoretical yield) ofB-3-methoxy-4-chlorophenylethylamine hydrochloride having a meltingpoint of 164 to 166 C. are obtained.

11. N-methyl-B-3-methoxy-4-chlorophenylethylamine,8-3-methoxy-4-chlorophenylethylamine hydrochloride (155.5 g; 0.7 mol)obtained in Part 1 is converted into the free base and treated in themanner described in Example 1 (a) l with formic acid. Subsequentlyreduction of the formamide thus obtained is effected with lithiumalanate in an atmosphere of nitrogen. 147 g (89% of the theoreticalyield) N-methy1-B-3-methoxy- 4-chlorophenylethylamine hydrochloridehaving a melting point of 147 to 148 C. are obtained.

b. Preparation of the end product 7-(3-bromopropyl)-theophylline (150.6g: 0.5 mol) and the free base obtained from 111.0 g (0.5 mol)N-methyl-B-3-methoxy-4-chlorophenylethylamine hydrochloride arecondensed as described in Example 9 with triethylamine and worked up.The toluene solu-. tion of the required end products is neutralized withhydrogen chloride gas and the precipitated salt is recrystallized fromethanol. A yield of 152.5 g. representing 67% of the theoretical yieldof 7-[N-methyl-N-( B-3- methoxy-4-chlorophenylethyl )-3-aminopropyl-theophylline hydrochloride having a melting point of 232 to 235 C. isobtained.

EXAMPLE 16 7-[ N-methyl-N-( B-Z-chloro-3-methoxyphenylethyl )-3-aminopropyl ]theophy11ine a. Preparation of the starting material 1.2-chloro-3-methoxybenzyl alcohol 2-chloro-3-methoxybenzoic acid (151 g;0.81 M) [Gibson .1. Chem. Soc. London (1926) 1428] is dissolved in 600mltetrahydrofuran and. over a period of minutes, added dropwise to amixture of 37 g lithium alanate (1.6 X 0.75 X 0.81 mol) andtetrahydrofuran (2:1) boiling under reflux. Boiling under reflux is thencontinued for a further 30 minutes. The reaction mixture is thendecomposed by the successive dropwise addition of water and soda lye.The precipitated aluminum hydroxide is filtered off under suction andthe filtrate is evaporated. As residue. 132 g (95% of the theoreticalyield) of 2-chloro-3-methoxybenzylalcohol, which is a bright yellowviscous oil, are obtained.

11. 2-chloro-3-methoxybenzyl chloride The 2-chloro-3-methoxybenzylalcohol (132 g; 0.76 mol) is dissolved in 300 ml. toluene. the solutionbeing stirred and cooled in ice for a period of 1 hour while thionylchloride 100 g; 1. 1 X 0.76 mol) is added dropwise. Subsequently. thesolution is boiled under reflux 16 for 1 hour. the solvent is evaporatedoff in vacuo and the residue is purified 'by fractional distillation.The fraction distilling over between 1 10 and C/ 1 Torr has an 11 of1.5610 and is collected. There is thus obtained 74 g. which is 51% ofthe theoretical yield, of 2-chloro-3-methoxybenzyl chloride.

[11. 2-chloro-3-methoxybenzyl cyanide The 2-chloro-3 methoxybenzylchloride (49g; 0.26 mol) obtained in Part 11 is added dropwise over aperiod of 30 minutes at 30 C. with stirring to a suspension of sodiumcyanide 1.1 X 0.262 mol) 66 ml. in dimethyl sulfoxide. Stirring iscontinued for an additional 2 hours. The reaction mixture is then pouredinto 250 ml. water and extracted with ether. The combined ethersolutions, after drying and evaporation, leave the crude nitrile. whichis purified by vacuum distillation. There are thus obtained 36 g. whichis 77% of the theoretical yield. of 2-chloro-3-methoxybenzyl cyanidehaving a boiling point of C/O.1 Torr.

IV. 8-2-chloro-3-methoxyphenylethylamine By catalytic hydrogenation ofthe 36 g (0.2 mol) of the above obtained 2-chloro-3-methoxybenzylcyanide. by the method described in Example 8 (a) 1, there are obtained36.5 g. which is 98% of the theoretical yield. ofB-2-chloro-3-methoxyphenylethylamine hydrochloride having a meltingpoint of 124 to 126 C.

V. N-methyl-B-Z-chloro-3-methoxyphenylethylamine The 36.5 g (0.164 mol)of the thus obtained hydrochloride is converted into the base. Thislatter, in the manner described in Example 1 (a) I. is reacted withformic acid to form the formamide. which by subsequent treatment withlithium alanate is converted intoN-methyl-B-2-chloro-3-methoxyphenylethylamine. There are thus obtained24.5 g. which is 74% of the theoretical yield, having a boiling point of90 to 95 C/0.3 Torr and an r1 of 1.5394. The hydrochloride melts at 192to 195 C.

b. Preparation of the end product 7-(3-bromopropyl)-theophylline (33.2g; 0.12 mol) and N-methyl-,B-Z-chloro-3-methoxyphenylethylamine 22.0 g;0.12 mol) are condensed with triethylamine in the manner described inExample 9, and worked up. The toluene solution of the base isneutralized with hydrogen chloride gas, which causes the hydrochlorideto be precipitated. This is then dissolved and allowed to crystallizefrom ethanol. The hydrochloride melts at 245 to 248 C. A yield of 32.2g. representing 64% of the theoretical yield. of7-[N-methyl-N-(B-2-chloro-3-methoxyphenylethyl)-3aminopropyl]-theophyl1ine hydrochloride isobtained.

EXAMPLE l7 7-[N-methyl-N-( B-3 .4-dich1orophenylethyl)-3-aminopropylltheophylline a. Preparation of the starting material 1. 7-[ 3-( N-methyl-N-benzyl )-aminopropyl]-theophylline7-(3-bromopropyl)-theophylline (301.2 g; 1 mol) and N-methylbenzylamine(242.3 g; 2 mol) are heated for 2 hours in an atmosphere of nitrogen,with stirring to a temperature of to C. After the temperature hasdropped to about 1 10 C., 2 l. toluene are added and the mixture isheated under reflux for 30 minutes. A fine crystalline deposit of 202 gN-methylbenzylamine hydrobromide, having a melting point of 160 C., isprecipitated and separated off. The toluene solution is washed withwater and then, by shaking with hydrochloric acid (1050 ml; 1N), isextracted. The aqueous hydrochloric acid phase precipitates the base onaddition of 40% soda lye. This is dissolved in toluene and, afterevaporation of the solvent, is distilled in vacuo. At 220 C/0.03 Torr,31 1 g, representing 91% of the theoretical yield, of 7-[3-(N-methyl-N-benzyl)-aminopropyl]-theophylline distils over as a viscousbright yellow oil having an n,, of 1.5748. The base is precipitated fromethanol and melts at 86 to 88 C. The hydrochloride, after beingdissolved in ethanol and allowed to crystallize, melts at 214.5 to 216C.

11. 7-( 3-methylaminopropyl )-theophylline Palladium-carbon-catalyst g;10%) is prehydrogenated in ethanol 100 ml). There is then added theretoa solution of 7-[3-N-methyl-N-benzyl)-aminopropyl]-theophylline (204.6g; 0.6 mol) in 400 ml. ethanol which is shaken at 40 C. with hydrogen.The calculated quantity of hydrogen is absorbed within 6 hours. Afterseparating the catalyst and evaporating the ethanol, an oil remainswhich is distilled in vacuo. At 192 to 194 C/0.03 Torr, 137 g, which is91% of the theoretical yield, of 7-(3-methylaminopropyl)-theophyllinehaving an n of 1.5588 distils over. This has a melting point of 625 to645 C. and the hydrochloride melts at 265 C.

111. 13-3,4-dichlorophenylethyl chloride To a solution of thionylchloride (424.0 9; 1.1 X 3.24 mol) in 300 ml. diethylether, is addeddropwise, in a period of 2 hours, a mixture ofB-3,4-dichlorophenylethanol (618.5 g; 3.24 mol) [R. Fuchs, J. Am. Chem.Soc. 78, 5612 (1956)], dry pyridine (256.2 g; 3,24 mol) and 500 ml.diethylether. The mixture is boiled, the ether being distilled off. Themixture is then heated on a water bath until about 500 ml. distillatehave been collected, the reaction mixture temperature rising to about 85C. After the addition of 42 g thionyl chloride, stirring is continuedfor a further 2 hours at this temperature. The reaction mixture is thendissolved in l l. ether and poured into 1 l. iced water. The aqueous andethereal layers are separated, and the aqueous portion is shaken twicemore with ether. The combined ether extracts are washed with water andsodium bicarbonate solution, dried with calcium chloride and evaporated.The residue distils over at 142 to 145 C/ l 1 Torr as a colorless oilhaving an n of 1.5631. The yield amounts to 602 g, which is 80% of thetheoretical yield.

b. Preparation of the end product The 7(3-methylaminopropyl)-theophylline 158.8 g; 2 X 0.316 mol) obtained fromPart 11 and B-3,4- dichlorophenylethyl chloride (66.1 g; 0.316 mol)obtained from Part 111 are heated together to 145 C. with stirring for 3hours. The mixture is allowed to cool to 1 10 C., whereupon l l. tolueneis added and the mixture is boiled for 30 minutes under reflux. 7-(3-methylaminopropyl)-theophylline hydrochloride (90 g) is precipitated andfiltered off under suction. 1t melts at 263 to 265 C. The toluenefiltrate is washed with water and then the desired end product isextracted by stirring with hot hydrochloride acid (2.7 1.; 0.1N). Theaqueous acid solution is then mixed with 40% soda lye,

the thus precipitated base is dissolved in toluene and drying iseffected by means of potassium carbonate. After evaporation of thesolvent, there remains 103 g.7-[N-methyl-N-(,8-3,4-dichlorophenylethyl)-3-aminopropyl]-theophylline.A sample distilled in a bulb tube distils at 210 to 220 C/0.00l Torr(air bath temperature) as a pale yellow highly viscous oil and has an 21of 1.5840.

1f the base (92 g) is dissolved in a hot mixture of 150 ml. ethanol and300 ml. ethyl acetate, and hydrogen chloride gas is bubbled through toproduce a low acid reaction, 95 g of the hydrochloride salt areprecipated. This is dissolved and allowed to crystallize from methanol.91 g hydrochloride having a melting point of 226 to 228 C. are obtained,which prove on chromatographic analysis to be pure.

EXAMPLE l8 7-[N-methyl-N-(13-3-chloro-4-methoxyphenylethyl )-3-aminopropyl ]-theophylline a. Preparation of the starting substance 1.B-3-chloro-4-methoxy-phenylethyl chloride B-3-ch1oro-4-methoxyphenylethanol (750 g; 4.02 mol) [L. S. Fosdick et al., J. Org. Chem. 68,842

(1946)] is chlorinated by the method described in- Example 17 (a) 111,by treatment with thionyl chloride and pyridine in adiethylether-solution. After working up, there are obtained 770.6 g,representing 94% of the theoretical yield, of,8-3-chloro-4-methoxyphenylethyl chloride having a boiling point of 102C/0.005 Torr and an n,; of 1.5555.

b. Preparation of the end product yield of the hydrochloride iscalculated to be 74% of the theoretical yield.

EXAMPLE 19 7-[N-methyl-N-( 13-3 ,4-dichlorophenylethyl-3-aminopropyl]theophylline a. Preparation of the starting material In a three-neckedflask, B-3,4-dichlorophenylethylamine (38 g; 0.2 mol) [F. Bennington etal., J. Or. Chem. 25, 2066 (1960)] and triethylamine (20.2 g; 0.2 mol)are mixed with ml. toluene. While stirring at room temperature and overa period of 90 minutes, a suspension of 7-(3-bromopropyl)-theophylline(60.2 g; 0.2 mol) in 300 m1. toluene is introduced and the mixture issubsequently boiled for 16 hours under reflux. The precipitatedtriethylamine hydrobromide (possibly formed fromB-3,4-dichlorophenylethylamine hydrobromide) is filtered off undersuction, the filtrate is washed with water and evaporated in vacuo. Theoily residue is then dissolved in 100 ml. isopropanol. After addingaqueous hydrobromic acid ml.; 48%), crystals are precipitated, which areisolated and then dissolved and allowed to recrystallize from methanol.57.5 g, representing 59% of the theoretical yield, of 7-[N-(13-3,4-dichlorophenylethyl)-3-aminopropyl]-theophylline-3-hydrobromidehaving a melting point of 243 to 245 C., are obtained.

b. Production of the end product 7- N-( B-3 ,4-dichlorophe nylethyl)-3-aminopropyl]theophylline (40.4 g; 0.1 mol) regenerated from thehydrobromide obtained in Part a is dissolved in 370 ml. ethanol and ismixed with formic acid (7.4 g; 1.6 X 0.1 mol). Aqueous formalin solution(40%, 1 1.1 g; 1.3 X 0.1 mol) is added and the mixture is boiled for 2hours under reflux. The residue after evaporation of the reactionsolution in dilute hydrochloric acid and shaken with toluene. From theaqueous acid solution, the base is separated out with soda lye,dissolved in toluene and dried. By passing hydrogen chloride gas intothe toluene solution, there is precipitated 7-[N- methyl-N-( B-3,4-dichlorop henylethyl 3-aminopropyl theophylline' hydrochloride.Recrystallization is effected from isopropanol. There are thus obtained39.3 g, representing 82% of the theoretical yield, of the salt having amelting point of 225 to 228 C.

Thesame result is obtained if the alcoholic solution of the7-[N-([3-3,4-dichlorophenylethyl)-3-aminopropyl]-theophylline is mixedwith a calculated quantity of formalin solution and heated for 2 hourson a water bath with sodium borohydride or is shaken with hydrogen and apalladium-carbon-catalyst at 40 C.

EXAMPLE 7-[ N-methyl-N-( B-3-chloro-4-hydroxyphenylethyl )-3-aminopropyl]theophylline 7-[N-methyl-N-( B-3-chloro-4-methoxyphenylethyl3-aminopropyl]-theophylline (56.1 g; 0.13 mol) prepared as described inExamples 14 and 18, is boiled under reflux for 2 hours with 120 ml. 48%aqueous hydrobromic acid (density 1.5) corresponding to 96.4 g HBr (2.18X 2 X 0.13 mol). A further 60 ml. of 48% hydrobromic acid of (4.1 X 0.13mol) is added and boiling is continued for a further hour. The reactionmixture is then poured into 1 l. iced water and accurately neutralizedwith 40% soda lye. The phenolic base is precipitated as an oil, whichcrystallizes on standing. The substance is dissolved in 2N hydrochloricacid. whereupon the hydrochloride precipitates out in the form of whitecrystals. After dissolving and recrystallizing from acetone there areobtained 25.2 g, which is 41% of the theoretical yield. of7-[N-methyl-N-(B-3- ehloro4-hydroxyphenylethyl )-3-aminopropyl]-theophylline hydrochloride having a melting point of 1 14 to 1 16 C.

EXAMPLE 21 7-[ N-methyl-N-( B-3-hydro xy-4-chlorophenylethyl )-3-aminopropyl]theophylline In a manner similar to that described inExample 20, 7-[N-methyl-N-(B-3-methoxy-4-chlorophenylethyl)-3-aminopropyl]theophylline 10.7 g; 0.23 mol), prepared as in Example 15 issubjected to ether cleavage with 34.4 ml. 48% aqueous hydrobromic acid.The crude phenolic base obtained after working up is dissolved inacetone and mixed with the solution of maleic acid (3.5 g) in acetone.The crystals, which are precipitated after 20 a short time, aredissolved and recrystallized from acetone. 43 g, representing 32% of thetheoretical yield, of 7-[ N-methyl-N-( 5-3-hydroxy-4-chlorophenylethyl)-3- aminopropyl]-theophylline maleate having a melting point of 190 to193 C. are obtained.

EXAMPLE 22 7-[N-me thyl-N-( ,8-2-chloro-3-hydroxyphenylethyl )-3-aminopropyl]theophylline7-[N-methyl-N-(B-Z-chloro-3-methoxyphenylethyl)-3-aminopropyl]-theophylline (30.1 g; 0.072 mol), produced as describedin Example 16, is boiled under reflux with 97 ml. 48% aqueoushydrobromic acid for 4 hours and worked up as described in Example 21.There are thus obtained 8.8 g, representing 24% of the theoreticalyield, of 7-[N-methyl-N-(,8-2-chloro-3-hydroxyphenylethyl)-3-aminopropyl]-theophylline maleate, which afterbeing dissolved and crystallized from acetone, melts at 195 to 196 C.

EXAMPLE 23 7-[N-methyl-N-( 13-3 ,4-dihydroxyphenylethyl )-3-aminopropyl]theophylline In a three-necked flask,7-(methyl-N-homoveratryl3- aminopropyl)-theophylline hydrochloride (226g; 0.5 mol) is mixed with 672 ml. 48% aqueous hydrobromic acid (density1.5), which are equivalent to 485g HBr (4 X 3 X 0.5 mol), and themixture is boiled under an atmosphere of nitrogen. Even at C., a livelybromomethane reaction occurs, which after boiling for 3 hours underreflux, terminates. 96% of the calculated bromoethane quantity is splitoff. The clear solution sets on cooling into a thick crystalline slurrywhich is extracted and washed with isopropanol. There are thus obtained248 g of the hydrobromide of the phenol base, which contains water ofcrystallization. By dissolving and recrystallizing a sample of this saltfrom methanol, there is formed the anhydrous salt having a melting pointof 238 C.

The above hydrobromide (100 g) is dissolved in 2.5 1. hot water. Aftercooling to room temperature, 500 ml. ammonia (2N) are added under anatmosphere of nitrogen, whereupon a pale-pink colored substance of oilyconsistancy is precipitated. The aqueous phase is decanted off, thesubstance is washed with water and dissolved in 2 1. ethanol. An excessof hydrogen chloride gas is bubbled into the filtered solution, which isclear, whereupon 78 g of7-[N-methyl-N-(B-3,4-dihydroxyphenyl)-3-aminopropyl]-theophyllinedihydrochloride are precipitated as a white crystalline powder having amelting point of 208 to 213 C. The yield obtained represents 84% of thetheoretical yield. If a 5% aqueous solution of the dihydrochloride (pl-11.0) is mixed with 1 equivalent of soda lye, there is obtained anaqueous solution of the monohydrochloride, which has a pH of 6.7. Themonohydrochloride, in water or methanol, gives a dark green colorationwith ferric (lIl) chloride, which becomes violet on the addition of sodalye.

EXAMPLE 24 7-[ N-methyl-N-( ,B-3-fluoro-4-hydroxyphenylethyl )-3-aminopro'pyl]theophylline 7-[N-methyl-N-(B-3-f1uoro-4-methoxyphenylethyl 3-aminopropyl]-theophyllinehydrochloride (60.3 g; 0.137- mol), prepared as described in Example 7and 123 ml. 48% aqueous hydrobromic acid (density 1.5 which isequivalent to 89 g HBr (4 X 2 X 0.137 mol) are boiled under reflux in around-bottomed flask for hours. After 3 hours the calculated quantity ofbromoethane has split off. The colorless solution obtained is mixed withan equal volume of diethylether, whereupon7-[N-methyl-N-(,B-3-fluoro-4-hydroxyphenylethyl)-3-aminopropyl]theophyllinehydrobromide separates out in crystalline form. After dissolving andcrystallizing from isopropanol, there are obtained 59.4 g, which is 92%of the theoretical yield, of the salt as a white crystalline powderhaving a melting point of 725 to 75 C. On further heating, the meltresolidifies at about 145 C. and then re-melts at 225 to 227 C.

The above hydrobromide (53.6 g; 0.11 mol) is dissolved in 1.3 l. warmwater and, by adding 1 14 ml. 1N soda lye dropwise under an atmosphereof nitrogen, the pH of solution is adjusted to 7.0. 43.5 g of the baseare precipitated as a white crystalline powder having a melting point of130 to 132 C. After dissolving and crystallizing from isopropanol, themelting point does not change. A solution of the base in methanol givesa yellow-red coloration with ferric (lIl) chloride. If the dried base isdissolved in methanol and hydrogen chloride gas is bubbled through untila weak acid reaction takes place, the'hydrochloride separates out as awhite crystalline powder. This powder, after dissolving andcrystallizing from a water/ethanol mixture (1:5), melts at 234.5 to 237C. A solution of this compound in water gives a yellow coloration withferric (llI) chloride while a methanolic solution gives a pale violetcoloration.

EXAMPLE 25 On a tablet press, tablets are pressed in a known mannerhaving the following composition;

100.00 mg. 7-[N-methyl-N-(B 3,4-dichlorophenylethyl )-3-aminopropyl-theophylline hydrochloride 50.00 mg. corn starch 4.50 mg. gelatine15.00 mg. lactose 7.50 mg. talc 0.75 mg. Aerosil (R.T.M.) which ischemically pure silicic acid in a submicroscopically fine distribution2.25 mg. potato starch (in the form of a thin 6% paste) EXAMPLE 26Coated pills of the following composition are produced in a knownmanner:

10.00 mg.7-[N-methyl-N-(B-2,6-dichlorophenylethyl)-3-aminopropyl]-theophyllinehydrochloride 50.00 mg. carrier 40.00 mg. sweetening composition Thecarrier comprises 9 parts corn starch,3 parts lactose and 1 partLuviskol (R.T.M.) VA 64 (a vinylpyrrolidone-vinyl acetate mixedpolymerisate in a 60:40 ratio, as described in Pharm. 1nd. 1962, 586.The sweetening composition consists of 5 parts cane sugar, 2 parts cornstarch, 2 parts calcium carbonate and 1 part talc. The pills so producedare subsequently pro vided with a gastric juice resistant coating.

EXAMPLE 27 7-[N-methyl-N-( [3-2,4-dichlorophenylethyl )-3-aminopropyl]-theophylline hydrochloride (2.0 mg.) is dissolved in 2.0ml.water, standardized isotonically with sodium chloride, and is filled ina sterile manner in ampoules of 2 ml. capacity.

We claim: I l. 7-[N-methyl-N-( B-3,4-dichlorophenylethyl )-3-aminopropyl]-theophylline.

2. 7-[N-methyl-N-(B-3-chloro-4-hydroxyphenylethyl)-3-aminopropyl]-theophylline.

1.7-(N-METHYL-N-(B-3,4-DICHLOROPHENYLETHYL)-3-AMINOPROPYL)-THEOPHYLLINE.2. 7-(N-methyl-N-( Beta-3-chloro-4-hydroxyphenylethyl)-3-aminopropyl)-theophylline.